# Epigenetic modulation of T cell tolerance in Multiple Sclerosis autoimmunity

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2020 · $438,928

## Abstract

PROJECT SUMMARY/ABSTRACT
Multiple Sclerosis (MS) is the leading cause of non-traumatic disability in young adults, therapies have limited
efficacy and there is no cure. In MS and its mouse model Experimental Autoimmune Encephalomyelitis (EAE),
inflammatory T helper (Th)1 and Th17 T cells promote a pathogenic inflammatory neural environment while
Th2 and regulatory T cells (Treg) are beneficial. Strategies that inhibit methylation reactions suppress
inflammation and Experimental Autoimmune Encephalomyelitis (EAE). These effects have been attributed to
inhibition of Protein Arginine Methyl Transferases (PRMT), a family of enzymes that regulate gene expression
and activity by catalyzing arginine methylation on histones and other proteins. However, lack of understanding
of which and how PRMTs modulate T cell effector function and lack of selective arginine
methyltransferase inhibitors has so far prevented further advancement in the field, as well as the
clinical application of these findings. We have developed first-in-class PRMT5-specific inhibitors. These
inhibitors suppressed EAE and pro-inflammatory Th1/Th17 cell responses while maintaining/increasing
Treg/Th2 responses. We hypothesize that PRMT5-mediated symmetric dimethylation reactions
contribute to autoimmunity by promoting and sustaining inflammatory T cell responses. Taking
advantage of the unique combination of expertise in molecular mechanisms of T cell phenotype and EAE
autoimmunity (Guerau), PRMT5-specific inhibitor drugs/signaling pathways (Baiocchi) and novel CRISPRi
technology (Han), we propose to identify a mechanism for methylation-promoted autoimmunity by dissecting
the role of PRMT5 on specific pathways that drive T cell inflammatory responses. Using both in vitro and
preclinical in vivo models of myelin-specific T cell driven MS disease, we propose to: 1) define the signals and
regulatory mechanisms governing PRMT5 expression during CD4 T cell activation/differentiation into
inflammatory vs. regulatory phenotypes, 2) determine the mechanistic consequences of PRMT5 activity on
inflammatory T cell responses and 3) determine the impact of T cell-specific PRMT5 modulation on clinical
disease activity in the adoptive transfer EAE mouse model of MS. These experiments will determine the role of
PRMT5 in the development and pathogenic potential of myelin-specific T cell responses that lead to CNS
autoimmunity. At the completion of these aims, we will have learned how PRMT5-catalyzed arginine
methylation shapes the phenotype and expansion of T cells and how these effects shape the adaptive immune
response to myelin antigens. These experiments will be the first to address the role of PRMT5 in inflammatory
autoimmune T cell responses and disease with novel specific drugs. Since both mouse and human PRMT5 are
highly conserved and targeted by these drugs, these studies could translate to novel therapeutic strategies to
treat MS and other autoimmune diseases.

## Key facts

- **NIH application ID:** 9926829
- **Project number:** 5R01AI121405-05
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Mireia Guerau-de-Arellano
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $438,928
- **Award type:** 5
- **Project period:** 2016-06-20 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926829

## Citation

> US National Institutes of Health, RePORTER application 9926829, Epigenetic modulation of T cell tolerance in Multiple Sclerosis autoimmunity (5R01AI121405-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9926829. Licensed CC0.

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